Roles proposed for nitric oxide (NO) in the CNS are increasingly diverse and range from intercellular signalling, through the killing of cells and invading pathogens, to the involvement of NO in programmed cell death and tissue remodelling. In experimental animal models of a variety of human neurophathologies, including stroke, there is evidence for upregulation of the genes coding for the three isoforms of NO synthase (NOS). In some of these neuropathologies it is clear that NO from a specific NOS isoform, expressed in a particular cell type, can contribute to damage. As a result there is increasing interest in deriving NOS isoform-selective inhibitors as potential therapeutic agents. On the other hand, in specific CNS pathologies NO has properties predicted to be beneficial and, therefore, determining and apportioning its role is and imperative. The long-term objective of this program is to determine how the NOS-2 gene is regulated in the CNS and roles for the resulting NO in pathophysiology. The immediate foal is to examine NOS-2 expression following transient and permanent meddle cerebral artery occlusion, models of focal ischemia in which pathological outcomes mirror the cognitive and sensorimotor deficits seen in humans following stroke. Using wildtype mice and NOS-2 gene-deficient littermates, hypotheses will be tested concerning the roles of cytokines and steroids in the regulation of NOS-2 expression, and the contribution of the resulting NO to pathological outcome Specifically, to identify (1) activators and (2) suppressors of the NOS-2 gene following ischemia, and then observe the effects on ischemic pathology of manipulating these proteins. Currently, there is no suitable drug to provide neuroprotection after human stroke. These studies will not only reveal roles for NO in the onset and recovery from damage following ischemia but may also provide the basis for novel and rational therapeutics.